ES2312921T3 - CONCENTRATED WATERPROOF DISSOLUTION OF AMBROXOL. - Google Patents
CONCENTRATED WATERPROOF DISSOLUTION OF AMBROXOL. Download PDFInfo
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- ES2312921T3 ES2312921T3 ES04078366T ES04078366T ES2312921T3 ES 2312921 T3 ES2312921 T3 ES 2312921T3 ES 04078366 T ES04078366 T ES 04078366T ES 04078366 T ES04078366 T ES 04078366T ES 2312921 T3 ES2312921 T3 ES 2312921T3
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- ambroxol
- aqueous solution
- solution according
- ammonium
- surfactant
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- 229960005174 ambroxol Drugs 0.000 title claims abstract description 28
- JBDGDEWWOUBZPM-XYPYZODXSA-N ambroxol Chemical compound NC1=C(Br)C=C(Br)C=C1CN[C@@H]1CC[C@@H](O)CC1 JBDGDEWWOUBZPM-XYPYZODXSA-N 0.000 title claims abstract description 28
- 238000004090 dissolution Methods 0.000 title description 3
- 239000007864 aqueous solution Substances 0.000 claims abstract description 22
- 239000002253 acid Substances 0.000 claims abstract description 12
- 239000004094 surface-active agent Substances 0.000 claims abstract description 11
- 150000003839 salts Chemical class 0.000 claims abstract description 10
- 125000001931 aliphatic group Chemical group 0.000 claims abstract description 4
- 125000003158 alcohol group Chemical group 0.000 claims abstract 2
- 239000000243 solution Substances 0.000 claims description 11
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 claims description 9
- 239000002324 mouth wash Substances 0.000 claims description 7
- NOOLISFMXDJSKH-UTLUCORTSA-N (+)-Neomenthol Chemical compound CC(C)[C@@H]1CC[C@@H](C)C[C@@H]1O NOOLISFMXDJSKH-UTLUCORTSA-N 0.000 claims description 5
- NOOLISFMXDJSKH-UHFFFAOYSA-N DL-menthol Natural products CC(C)C1CCC(C)CC1O NOOLISFMXDJSKH-UHFFFAOYSA-N 0.000 claims description 5
- 229940041616 menthol Drugs 0.000 claims description 5
- 229940051866 mouthwash Drugs 0.000 claims description 5
- 239000007921 spray Substances 0.000 claims description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 3
- VTAJIXDZFCRWBR-UHFFFAOYSA-N Licoricesaponin B2 Natural products C1C(C2C(C3(CCC4(C)CCC(C)(CC4C3=CC2)C(O)=O)C)(C)CC2)(C)C2C(C)(C)CC1OC1OC(C(O)=O)C(O)C(O)C1OC1OC(C(O)=O)C(O)C(O)C1O VTAJIXDZFCRWBR-UHFFFAOYSA-N 0.000 claims description 3
- 150000003863 ammonium salts Chemical class 0.000 claims description 3
- LPLVUJXQOOQHMX-UHFFFAOYSA-N glycyrrhetinic acid glycoside Natural products C1CC(C2C(C3(CCC4(C)CCC(C)(CC4C3=CC2=O)C(O)=O)C)(C)CC2)(C)C2C(C)(C)C1OC1OC(C(O)=O)C(O)C(O)C1OC1OC(C(O)=O)C(O)C(O)C1O LPLVUJXQOOQHMX-UHFFFAOYSA-N 0.000 claims description 3
- 229960004949 glycyrrhizic acid Drugs 0.000 claims description 3
- UYRUBYNTXSDKQT-UHFFFAOYSA-N glycyrrhizic acid Natural products CC1(C)C(CCC2(C)C1CCC3(C)C2C(=O)C=C4C5CC(C)(CCC5(C)CCC34C)C(=O)O)OC6OC(C(O)C(O)C6OC7OC(O)C(O)C(O)C7C(=O)O)C(=O)O UYRUBYNTXSDKQT-UHFFFAOYSA-N 0.000 claims description 3
- 239000001685 glycyrrhizic acid Substances 0.000 claims description 3
- 235000019410 glycyrrhizin Nutrition 0.000 claims description 3
- LPLVUJXQOOQHMX-QWBHMCJMSA-N glycyrrhizinic acid Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@H](O[C@@H]1O[C@@H]1C([C@H]2[C@]([C@@H]3[C@@]([C@@]4(CC[C@@]5(C)CC[C@@](C)(C[C@H]5C4=CC3=O)C(O)=O)C)(C)CC2)(C)CC1)(C)C)C(O)=O)[C@@H]1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O LPLVUJXQOOQHMX-QWBHMCJMSA-N 0.000 claims description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 2
- SHBUUTHKGIVMJT-UHFFFAOYSA-N Hydroxystearate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OO SHBUUTHKGIVMJT-UHFFFAOYSA-N 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims description 2
- 229940072106 hydroxystearate Drugs 0.000 claims description 2
- 229960003511 macrogol Drugs 0.000 claims description 2
- 208000024891 symptom Diseases 0.000 description 5
- 206010044008 tonsillitis Diseases 0.000 description 5
- 239000000203 mixture Substances 0.000 description 4
- QNVKOSLOVOTXKF-UHFFFAOYSA-N 4-[(2-amino-3,5-dibromophenyl)methylamino]cyclohexan-1-ol;hydron;chloride Chemical compound Cl.NC1=C(Br)C=C(Br)C=C1CNC1CCC(O)CC1 QNVKOSLOVOTXKF-UHFFFAOYSA-N 0.000 description 3
- 206010013911 Dysgeusia Diseases 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 229960000985 ambroxol hydrochloride Drugs 0.000 description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- 239000000443 aerosol Substances 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000000902 placebo Substances 0.000 description 2
- 229940068196 placebo Drugs 0.000 description 2
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 2
- 239000012085 test solution Substances 0.000 description 2
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 2
- LDDMACCNBZAMSG-BDVNFPICSA-N (2r,3r,4s,5r)-3,4,5,6-tetrahydroxy-2-(methylamino)hexanal Chemical compound CN[C@@H](C=O)[C@@H](O)[C@H](O)[C@H](O)CO LDDMACCNBZAMSG-BDVNFPICSA-N 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- 206010022998 Irritability Diseases 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- 206010001093 acute tonsillitis Diseases 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000003172 expectorant agent Substances 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 230000000510 mucolytic effect Effects 0.000 description 1
- 229940066491 mucolytics Drugs 0.000 description 1
- 239000002736 nonionic surfactant Substances 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000008389 polyethoxylated castor oil Substances 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 235000011118 potassium hydroxide Nutrition 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 235000015424 sodium Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M sodium bicarbonate Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- 238000005507 spraying Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
- A61K9/006—Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/136—Amines having aromatic rings, e.g. ketamine, nortriptyline having the amino group directly attached to the aromatic ring, e.g. benzeneamine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
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- Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Physiology (AREA)
- Nutrition Science (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Agricultural Chemicals And Associated Chemicals (AREA)
- Detergent Compositions (AREA)
Abstract
Description
Disolución acuosa concentrada de ambroxol.Aqueous concentrated solution of ambroxol.
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La presente invención se refiere a una disolución acuosa concentrada de ambroxol.The present invention relates to a concentrated aqueous solution of ambroxol.
El ambroxol [trans-4-(2-amino-3,5-dibromobencilamino)ciclohexanol] es un fármaco mucolítico muy conocido que se encuentra en diversas composiciones apropiadas para la administración por vía oral o parenteral. Sin embargo, se prefieren claramente las composiciones orales.Ambroxol [trans-4- (2-amino-3,5-dibromobenzylamino) cyclohexanol] It is a well-known mucolytic drug found in various compositions suitable for oral administration or parenteral However, compositions are clearly preferred. oral
La solicitud de patente internacional WO 01/05378 da a conocer un comprimido para chupar en el tratamiento de síntomas de amigdalitis.WO international patent application 05/01378 discloses a tablet to suck in the treatment of symptoms of tonsillitis.
Posteriormente, se han publicado dos artículos (Deutsche Apotheker Zeitung; 17, 2113, 2002; J. Fischer et al. Arzneim. Forsch.; 52, 256. 2002) que se refieren a estudios controlados con utilización de placebo, aleatorizados y estadísticamente significativos, que demuestran la efectividad en los síntomas de amigdalitis de comprimidos que comprenden 20 ó 30 mg de ambroxol. Sin embargo, los autores consideran que las formas líquidas, tales como los enjuagues bucales y los aerosoles, no permiten que el ambroxol ejerza su efectividad en los síntomas de amigdalitis debido al corto período de permanencia en la boca.Subsequently, two articles have been published ( Deutsche Apotheker Zeitung ; 17, 2113, 2002; J. Fischer et al . Arzneim. Forsch .; 52, 256. 2002) that refer to controlled, randomized and statistically significant controlled studies , which demonstrate the effectiveness in the symptoms of tonsillitis of tablets comprising 20 or 30 mg of ambroxol. However, the authors consider that liquid forms, such as mouthwashes and aerosols, do not allow ambroxol to exert its effectiveness in the symptoms of tonsillitis due to the short period of permanence in the mouth.
Además, las formas líquidas acuosas actualmente disponibles no pueden desarrollar una acción suficiente debido a que la concentración de ambroxol es bastante baja debido a la poca solubilidad en agua del clorhidrato de ambroxol, que es aproximadamente del 3% (p/v).In addition, aqueous liquid forms currently available cannot develop sufficient action due to that the concentration of ambroxol is quite low due to the low water solubility of ambroxol hydrochloride, which is approximately 3% (w / v).
Por lo tanto, existe todavía una gran necesidad de una disolución acuosa, que no presente un olor y sabor desagradables, y que comprenda unas concentraciones elevadas de ambroxol.Therefore, there is still a great need of an aqueous solution, which does not have a smell and taste unpleasant, and that includes high concentrations of ambroxol
En una iniciativa para alcanzar dicho resultado, el presente solicitante investigó diversas disoluciones acuosas de sales de adición ácidas del ambroxol, tales como el clorhidrato de ambroxol, que comprendían agentes tensioactivos no iónicos estables que son muy conocidos en el campo farmacéutico y se utilizan con frecuencia asimismo en la preparación de composiciones acuosas inyectables, tales como alcoholes y ácidos alifáticos de las familias conocidas comercialmente con las marcas comerciales Cremophor^{TM} y Solutol^{TM}. Sin embargo, no resultó posible obtener disoluciones acuosas de clorhidrato de ambroxol con una concentración sustancialmente superior al 3% (p/v).In an initiative to achieve that result, The present applicant investigated various aqueous solutions of acid addition salts of ambroxol, such as hydrochloride ambroxol, which comprised stable nonionic surfactants which are well known in the pharmaceutical field and are used with frequency also in the preparation of aqueous compositions injectables, such as alcohols and aliphatic acids of the commercially known families with trademarks Cremophor ™ and Solutol ™. However, it was not possible obtain aqueous solutions of ambroxol hydrochloride with a concentration substantially greater than 3% (w / v).
Durante dichos ensayos, en cambio, se descubrió sorprendentemente que un incremento del valor del pH desde 4,5 a 5 hasta 6 a 6,5, o superior, permite obtener disoluciones con una concentración de clorhidrato de ambroxol superior al 3% (p/v). Generalmente, dichas disoluciones comprenden entre el 4% y el 7% (p/v).During these tests, however, it was discovered surprisingly, an increase in the pH value from 4.5 to 5 up to 6 to 6.5, or higher, allows solutions to be obtained with a Ambroxol hydrochloride concentration greater than 3% (w / v). Generally, said solutions comprise between 4% and 7% (p / v).
Por lo tanto un objetivo de la presente invención es proporcionar una disolución acuosa que comprenda una sal de adición ácida de ambroxol y un agente tensioactivo, siendo dicho agente tensioactivo un alcohol o ácido alifático etoxilado, el valor del pH se encuentre comprendido entre 6 y 7 y el contenido en ambroxol se encuentre comprendido entre el 4 y el 7% (p/v).Therefore an objective of the present invention is to provide an aqueous solution comprising a acid addition salt of ambroxol and a surfactant, being said surfactant an ethoxylated alcohol or aliphatic acid, the pH value is between 6 and 7 and the content in ambroxol it is between 4 and 7% (w / v).
Habitualmente, la sal de adición ácida de ambroxol es un clorhidrato.Usually the acid addition salt of Ambroxol is a hydrochloride.
En general, la disolución acuosa de la presente invención puede comprender principios farmacéuticamente activos adicionales cuya administración conjunta resulte útil siempre que no interfieran con la solubilidad de la sal de adición ácida de ambroxol en la disolución de la presente invención.In general, the aqueous solution of the present invention may comprise pharmaceutically active principles additional ones whose joint administration is useful provided that interfere with the solubility of the acid addition salt of Ambroxol in the solution of the present invention.
Preferentemente, sin embargo, una sal de adición ácida de ambroxol constituye el único principio farmacéuticamente activo de la disolución acuosa de la presente invención.Preferably, however, an addition salt Ambroxol acid constitutes the only pharmaceutically active of the aqueous solution of the present invention.
Ventajosamente, se alcanza un valor de pH comprendido entre 6 y 7 añadiendo una base inorgánica u orgánica, tal como hidróxido sódico o potásico, bicarbonato sódico o potásico, trietanolamina, Tris [tris(hidroximetil)aminometano], N-metilglucosamina, lisina, arginina y similares.Advantageously, a pH value is reached between 6 and 7 adding an inorganic or organic base, such as sodium or potassium hydroxide, sodium or potassium bicarbonate, triethanolamine, Tris [tris (hydroxymethyl) aminomethane], N-methylglucosamine, lysine, arginine and Similar.
Preferentemente, la cantidad de agente tensioactivo en la disolución de la presente invención está comprendida entre el 5 y el 20% (p/v). Más preferentemente entre el 8% y el 13% (p/v).Preferably, the amount of agent surfactant in the solution of the present invention is between 5 and 20% (w / v). More preferably between 8% and 13% (w / v).
Ventajosamente, el agente tensioactivo es el Solutol^{TM} 15 (hidroxiestearato de macrogol 15, Farmacopea Europea IV Edición).Advantageously, the surfactant is the Solutol ™ 15 (macrogol hydroxystearate 15, Pharmacopoeia European IV Edition).
Una ventaja adicional de la disolución de la presente invención es que es estable durante un largo período de tiempo. En un frasco oscuro a 25ºC es estable durante por lo menos 12 meses.An additional advantage of dissolving the present invention is that it is stable over a long period of weather. In a dark bottle at 25 ° C it is stable for at least 12 months.
Tal como resulta muy conocido, el ambroxol se caracteriza por un regusto particularmente amargo que va resultando más difícil de ocultar a medida que se incrementa la concentración. Por lo tanto, resulta particularmente difícil de ocultar el regusto del ambroxol incluso cuando los excipientes presentes en la disolución de la presente invención no presentan un sabor desagradable.As it is well known, ambroxol is characterized by a particularly bitter aftertaste that is resulting more difficult to hide as concentration increases. Therefore, it is particularly difficult to hide the aftertaste of ambroxol even when the excipients present in the Solution of the present invention does not present a taste unpleasant.
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El presente solicitante ha descubierto sorprendentemente que las sales amónicas del ácido glicirrícico son particularmente apropiadas para ocultar el regusto amargo del ambroxol. La sal preferida es el monoglicirricinato amónico.The present applicant has discovered surprisingly that the ammonium salts of glycyrrhizic acid are particularly appropriate to hide the bitter aftertaste of ambroxol The preferred salt is ammonium monoglycyrrhizinate.
En este sentido, se ha descubierto que la acción combinada del monoglicirricinato amónico con el mentol resulta particularmente efectiva.In this sense, it has been discovered that the action combined ammonium monoglycyrrhizinate with menthol results particularly effective
La proporción en peso preferida de monoglicirricinato amónico:mentol se encuentra comprendida entre 0,5:10 y 5:10.The preferred weight ratio of ammonium monoglycyrrhizinate: menthol is comprised between 0.5: 10 and 5:10.
A su vez, la proporción en peso preferida de monoglicirricinato amónico:ambroxol se encuentra comprendida entre 0,001:1 y 0,1:1. Más preferentemente, dicha proporción en peso se encuentra comprendida entre 0,01:1 y 0,05:1, aún más preferentemente se encuentra comprendida entre 0,011:1 y 0,025:1.In turn, the preferred weight ratio of ammonium monoglycyrrhizinate: ambroxol is between 0.001: 1 and 0.1: 1. More preferably, said weight ratio is is between 0.01: 1 and 0.05: 1, even more preferably it is between 0.011: 1 and 0.025: 1.
La disolución de la presente invención es apropiada para un tratamiento mucolítico en lugar de las composiciones conocidas basadas en el ambroxol. Sin embargo, unas investigaciones exhaustivas han demostrado que, sorprendentemente, la disolución de la presente invención resulta efectiva en el tratamiento de los síntomas de amigdalitis cuando se administra en forma de aerosoles o enjuagues bucales.The solution of the present invention is appropriate for a mucolytic treatment instead of known compositions based on ambroxol. However, some exhaustive research has shown that, surprisingly, the dissolution of the present invention is effective in the treatment of tonsillitis symptoms when administered in form of sprays or mouthwashes.
Las formas farmacéuticas preferidas de la disolución de la presente invención son, por lo tanto, aerosoles y enjuagues bucales.Preferred dosage forms of the dissolution of the present invention are therefore aerosols and mouthwash
Los siguientes ejemplos ilustran adicionalmente la presente invención, sin limitar la misma.The following examples further illustrate the present invention, without limiting it.
Ejemplo 1Example one
Una disolución según la presente invención comprende:A solution according to the present invention understands:
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Ensayo 1Test one
Se realizó un ensayo doble ciego en un grupo de 30 pacientes con amigdalitis aguda sin complicaciones que en 3 grupos de 10 pacientes cada uno a fin de mantener la aleatoriedad.A double blind trial was performed in a group of 30 patients with acute tonsillitis without complications than in 3 groups of 10 patients each in order to maintain the randomness
El primer grupo se trató con placebo, el segundo se trató con la disolución del ejemplo 1 en forma en enjuague bucal y el tercer grupo se trató con la disolución del ejemplo 1 en forma de aerosol.The first group was treated with placebo, the second it was treated with the solution of example 1 in the form of mouthwash and the third group was treated with the solution of example 1 in the form Spray
En el momento del análisis, se solicitó a los pacientes que expresaran el nivel de dolor en una escala desde 0 (= sin dolor) hasta 5 (= dolor muy intenso).At the time of the analysis, the patients expressing the level of pain on a scale from 0 (= no pain) up to 5 (= very intense pain).
El análisis se realizó antes del tratamiento y 30, 60, 120 y 180 minutos tras el tratamiento.The analysis was performed before treatment and 30, 60, 120 and 180 minutes after treatment.
En el caso del enjuague bucal, el tratamiento comprendía enjuagar la boca con la disolución del ensayo durante un minuto.In the case of mouthwash, the treatment it included rinsing the mouth with the test solution during a minute.
En el caso del aerosol, el tratamiento comprendía pulverizar 0,20 ml de la disolución del ensayo.In the case of the spray, the treatment It comprised spraying 0.20 ml of the test solution.
Resultados (intensidad del dolor en comparación con el placebo):Results (pain intensity compared with placebo):
- Enjuague bucal: 30 minutos (50%), 60 minutos (35%), 120 minutos (30%), 180 minutos (30%);Mouthwash: 30 minutes (50%), 60 minutes (35%), 120 minutes (30%), 180 minutes (30%);
- Aerosol: 30 minutos (47%), 60 minutos (34%), 120 minutos (28%), 180 minutos (27%).Spray: 30 minutes (47%), 60 minutes (34%), 120 minutes (28%), 180 minutes (27%).
Claims (14)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IT002463A ITMI20032463A1 (en) | 2003-12-16 | 2003-12-16 | AQUEOUS CONCENTRATED AMBROXOL SOLUTION |
| ITMI03A2463 | 2003-12-16 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| ES2312921T3 true ES2312921T3 (en) | 2009-03-01 |
Family
ID=34509469
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| ES04078366T Expired - Lifetime ES2312921T3 (en) | 2003-12-16 | 2004-12-10 | CONCENTRATED WATERPROOF DISSOLUTION OF AMBROXOL. |
Country Status (11)
| Country | Link |
|---|---|
| EP (1) | EP1543826B1 (en) |
| AT (1) | ATE406871T1 (en) |
| CY (1) | CY1108593T1 (en) |
| DE (1) | DE602004016274D1 (en) |
| DK (1) | DK1543826T3 (en) |
| ES (1) | ES2312921T3 (en) |
| IT (1) | ITMI20032463A1 (en) |
| PL (1) | PL1543826T3 (en) |
| PT (1) | PT1543826E (en) |
| RS (1) | RS50685B (en) |
| SI (1) | SI1543826T1 (en) |
Families Citing this family (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2012085185A1 (en) | 2010-12-23 | 2012-06-28 | Advance Holdings Limited | Aqueous solution of ambroxol |
| JP5930332B2 (en) | 2011-03-14 | 2016-06-08 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | Use of sprayable compositions comprising ambroxol |
| KR101915056B1 (en) * | 2012-04-10 | 2018-11-07 | 한미약품 주식회사 | Liquidic formulation for oral administraion comprising ambroxol, levodropropizine and buffer, and method for preparing the same |
| WO2015125757A1 (en) * | 2014-02-18 | 2015-08-27 | 大正製薬株式会社 | Internal liquid agent |
| CN104316482A (en) * | 2014-08-15 | 2015-01-28 | 河北菲尼斯生物技术有限公司 | A quality control method for ambroxol hydrochloride particles |
| WO2018182546A1 (en) | 2017-03-27 | 2018-10-04 | İlko Ilaç Sanayi Ve Ticaret Anonim Şirketi | Stabilized pharmaceutical syrup composition comprising terbutaline sulphate and ambroxol hydrochloride |
| CN110384656A (en) * | 2018-04-19 | 2019-10-29 | 上海现代药物制剂工程研究中心有限公司 | Edaravone nasal administration composition and its nasal administration formulation preparation method |
| WO2021005176A1 (en) | 2019-07-09 | 2021-01-14 | Genethon | Treatment of glycogen storage disease (gsd) |
| CN113995721A (en) * | 2020-07-27 | 2022-02-01 | 德国吉麦医疗技术有限公司 | Ambroxol hydrochloride oral spray solution and preparation method thereof |
| CN112168783A (en) * | 2020-10-26 | 2021-01-05 | 山东裕欣药业有限公司 | Oral medicine spray for respiratory system and preparation method thereof |
| CN112168782A (en) * | 2020-10-26 | 2021-01-05 | 山东裕欣药业有限公司 | Preparation method of respiratory system medicine oral spray |
| WO2024254058A1 (en) * | 2023-06-06 | 2024-12-12 | R.P. Scherer Technologies, Llc | Ambroxol liquid formulation |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU574360B2 (en) * | 1983-05-13 | 1988-07-07 | Reichert, D. | Antisnoring agent |
| DE3524003A1 (en) * | 1985-07-04 | 1987-01-08 | Heumann Ludwig & Co Gmbh | MEDICINE GRANULES WITH DELAYED ACTIVE SUBSTANCE RELEASE AND METHOD FOR THE PRODUCTION THEREOF |
| DE3610997A1 (en) * | 1986-04-02 | 1987-10-15 | Krewel Werke Gmbh | AMBROXOL NOSE SPRAY |
| IT1252185B (en) * | 1991-12-11 | 1995-06-05 | Therapicon Srl | PROGRAMMED LIBERATION PHARMACEUTICAL PREPARATIONS |
| DE19933148A1 (en) * | 1999-07-20 | 2001-01-25 | Boehringer Ingelheim Int | Lozenge containing ambroxol |
| EP1437134A4 (en) * | 2001-09-04 | 2009-03-11 | Boehringer Ingelheim Int | Anti-influenza drugs |
-
2003
- 2003-12-16 IT IT002463A patent/ITMI20032463A1/en unknown
-
2004
- 2004-12-10 DE DE602004016274T patent/DE602004016274D1/en not_active Expired - Lifetime
- 2004-12-10 PT PT04078366T patent/PT1543826E/en unknown
- 2004-12-10 AT AT04078366T patent/ATE406871T1/en active
- 2004-12-10 EP EP04078366A patent/EP1543826B1/en not_active Expired - Lifetime
- 2004-12-10 DK DK04078366T patent/DK1543826T3/en active
- 2004-12-10 SI SI200430933T patent/SI1543826T1/en unknown
- 2004-12-10 PL PL04078366T patent/PL1543826T3/en unknown
- 2004-12-10 ES ES04078366T patent/ES2312921T3/en not_active Expired - Lifetime
- 2004-12-10 RS RSP-2008/0563A patent/RS50685B/en unknown
-
2008
- 2008-11-26 CY CY20081101361T patent/CY1108593T1/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| RS50685B (en) | 2010-06-30 |
| SI1543826T1 (en) | 2009-02-28 |
| CY1108593T1 (en) | 2014-04-09 |
| ITMI20032463A1 (en) | 2005-06-17 |
| PL1543826T3 (en) | 2009-02-27 |
| ATE406871T1 (en) | 2008-09-15 |
| DE602004016274D1 (en) | 2008-10-16 |
| PT1543826E (en) | 2008-12-12 |
| EP1543826B1 (en) | 2008-09-03 |
| DK1543826T3 (en) | 2009-01-12 |
| EP1543826A1 (en) | 2005-06-22 |
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